8-140533039-T-C

Variant names:

• chr8-140533039-T-C
• rs2977462
• NM_012154.5:c.2272-424A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_012154.5(AGO2):​c.2272-424A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.493 in 149,186 control chromosomes in the GnomAD database, including 18,244 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.49 (18244 hom., cov: 28)
• Consequence: AGO2 NM_012154.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.48
• Publications: 3 publications found

Genes affected

AGO2 (HGNC:3263): (argonaute RISC catalytic component 2) This gene encodes a member of the Argonaute family of proteins which play a role in RNA interference. The encoded protein is highly basic, and contains a PAZ domain and a PIWI domain. It may interact with dicer1 and play a role in short-interfering-RNA-mediated gene silencing. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2009]

AGO2 Gene-Disease associations (from GenCC):

• Lessel-Kreienkamp syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Illumina, Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.564 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012154.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGO2	NM_012154.5	MANE Select	c.2272-424A>G		intron	N/A	NP_036286.2
	AGO2	NM_001164623.3		c.2170-424A>G		intron	N/A	NP_001158095.1	Q9UKV8-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGO2	ENST00000220592.10	TSL:1 MANE Select	c.2272-424A>G		intron	N/A	ENSP00000220592.5	Q9UKV8-1
	AGO2	ENST00000519980.5	TSL:1	c.2170-424A>G		intron	N/A	ENSP00000430176.1	Q9UKV8-2
	AGO2	ENST00000523609.5	TSL:1	n.*1857-424A>G		intron	N/A	ENSP00000430164.1	E5RGG9

Frequencies

GnomAD3 genomes AF: 0.493 AC: 73494 AN: 149092 Hom.: 18231 Cov.: 28

Gnomad AFR AF: 0.571

Gnomad AMI AF: 0.405

Gnomad AMR AF: 0.458

Gnomad ASJ AF: 0.472

Gnomad EAS AF: 0.371

Gnomad SAS AF: 0.485

Gnomad FIN AF: 0.421

Gnomad MID AF: 0.474

Gnomad NFE AF: 0.477

Gnomad OTH AF: 0.480

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.493 AC: 73548 AN: 149186 Hom.: 18244 Cov.: 28 AF XY: 0.490 AC XY: 35544 AN XY: 72612

African (AFR) AF: 0.570 AC: 23153 AN: 40584

American (AMR) AF: 0.458 AC: 6847 AN: 14950

Ashkenazi Jewish (ASJ) AF: 0.472 AC: 1629 AN: 3448

East Asian (EAS) AF: 0.371 AC: 1859 AN: 5016

South Asian (SAS) AF: 0.486 AC: 2307 AN: 4748

European-Finnish (FIN) AF: 0.421 AC: 4033 AN: 9588

Middle Eastern (MID) AF: 0.493 AC: 139 AN: 282

European-Non Finnish (NFE) AF: 0.477 AC: 32218 AN: 67596

Other (OTH) AF: 0.482 AC: 998 AN: 2072

Alfa AF: 0.478 Hom.: 31894

Bravo AF: 0.493

Asia WGS AF: 0.432 AC: 1501 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.57
DANN	Benign	0.54
PhyloP100		-1.5
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2977462; hg19: chr8-141543138;